Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the present invention belongs to the field of pharmaceutical synthesis, and particularly relates to an EGFR inhibitor, preparation method therefor and application thereof.
• Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
• Multi-target therapies against epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocations, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangements and B-raf proto-oncogenes, serine/threonine kinases (BRAF) have been successfully developed and clinically validated.
• Inhibitors against EGFR can significantly improve progression-free survival of adenocarcinoma in NSCLC, while acquired resistance mutations of these inhibitors can be targeted by the third generation EGFR inhibitors.
• Exon 20 Although classical EGFR activating mutations (Exons 19 and 21) and drug resistance mutation (T790M) can be inhibited by existing medicaments, but insertion mutation of Exon 20 also results in structural activation of EGFR signaling and is insensitive to all of existing EGFR inhibitors.
• the mutation of Exon 20 is heterogeneous and includes insertions or repeats of 1-7 amino acids between amino acids at positions 762-774 of the EGFR protein.
• the mutation frequency of Exon 20 in EGFR is 4-10% of all mutations in EGFR.
• the insertion mutation of EGFR Exon 20 is also seen in a rare head and neck cancer, namely sinonasal squamous cell carcinoma (SNSCC).
• SNSCC sinonasal squamous cell carcinoma
• a structurally-similar insertion mutation of Exon 20 is also found in HER2, another member of the EGFR family.
• the object of the present invention is to provide an EGFR inhibitor, preparation method therefor and application thereof.
• a series of compounds of the present invention have a strong inhibition effect on the cytological activity of an insertion, deletion or other mutation of EGFR Exon 20, have a high selectivity for EGFR wild type, and can be widely applied to the preparation of medicaments for treating and/or preventing cancer, tumor or metastatic disease at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20, particularly medicaments for treating hyperproliferative diseases and diseases for inducing cell death disorder, so that a new generation of EGFR inhibitors is expected to be developed.
• the first aspect of the present invention provides a compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof: wherein ring A is C 6-10 aryl or 5-10 membered heteroaryl;
• R 5 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterioalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 8 , -C 0-4 alkyl-O-R 9 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-O-C(O)R 11 , -C 0-4 alkyl-NR 12 R 13 , -C
• ring A is C 6-8 aryl or 5-8 membered heteroaryl; preferably, ring A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl and thiazolyl.
• the compound of formula (I) is a compound of formula (IIa), formula (IIb) or formula (IIc): or
• R is selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 deuterioalkyl;
• R 1 is vinyl or ethynyl, the vinyl or ethynyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluoro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteriomethyl, trideuteriomethyl, cyclopropyl, amino, dimethylamino and dimethylaminomethyl.
• R is hydrogen
• R 1 is vinyl, the vinyl is optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluoro, cyano, methyl and dimethylaminomethyl.
• each R 3 is independently selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, dideuteriomethyl, trideuteriomethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, trideuteriomethoxy, dideuteriomethoxy, cyclopropyl, cyclobutyloxy and amino.
• each R 4 is independently selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluoro, chloro, bromo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 deuterioalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.
• the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof include, but are not limited to, the following compounds:
• the second aspect of the present invention provides a process for preparing the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof, which comprises the following steps: wherein, ring A, X, Z 1 , Z 2 , L, R 1, R 2 , R 3 , R 4 and n are described as those in the compound of formula (I).
• the third aspect of the present invention provides a pharmaceutical composition, which comprises the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention also relates to use of the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof in preparation of a medicament for treating and/or preventing cancer, tumor or metastatic disease at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20.
• the present invention also relates to use of the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof in preparation of a medicament for preventing and/or treating tumor, cancer and/or metastatic disease caused by hyperproliferation and dysfunction in cell death induction.
• the present invention also relates to use of the above compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof in preparation a medicament for preventing and/or treating lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumors, urological tumor, skin tumor, sarcoma, sinonasal inverted papilloma or sinonasal squamous cell carcinoma associated with sinonasal inverted papilloma at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20.
• the present invention also relates to the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof for use in treatment and/or prevention of cancer, tumor or metastatic disease at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20.
• the present invention also relates to the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof for use in prevention and/or treatment of tumor, cancer and/or metastatic disease caused by hyperproliferation and dysfunction in cell death induction.
• the present invention also relates to the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof for use in treatment and/or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumors, urological tumor, skin tumor, sarcoma, inverted sinonasal papilloma or inverted sinonasal papilloma associated sinonasal squamous cell carcinoma at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20.
• the present invention also relates to a method for treating and/or preventing cancer, tumor or metastatic disease at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof.
• the present invention also relates to a method for preventing and/or treating tumor, cancer and/or metastatic disease caused by hyperproliferation and dysfunction in cell death induction, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof.
• the present invention also relates to a method for treating and/or preventing lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumor, thoracic tumor, gastrointestinal tumor, endocrine tumor, breast and other gynecological tumors, urological tumor, skin tumor, sarcoma, inverted sinonasal papilloma or inverted sinonasal papilloma associated sinonasal squamous cell carcinoma at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), the stereoisomer or pharmaceutically acceptable salt thereof.
• an EGFR inhibitor with a structure shown as formula (I).
• a series of compounds of the present invention can be widely applied to the preparation of medicaments for treating and/or preventing cancer, tumor or metastatic disease at least partially associated with an insertion, deletion or other mutation of EGFR Exon 20, particularly medicaments for treating hyperproliferative diseases and diseases for inducing cell death disorder, so that a new generation of EGFR inhibitors is expected to be developed.
• the present invention is achieved on this basis.
• Alkyl refers to linear or branched saturated aliphatic alkyl groups, preferably linear or branched alkyl groups containing 1 to 10, 1 to 6 or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n -propyl, isopropyl, n -butyl, isobutyl, tert-butyl, sec -butyl, n -pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n -hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl
• C 1-10 alkyl refers to linear alkyl and branched alkyl containing 1 to 10 carbon atoms
• C 1-4 alkyl refers to linear alkyl and branched alkyl containing 1 to 4 carbon atoms
• C 0-8 alkyl refers to linear alkyl and branched alkyl containing 0 to 8 carbon atoms
• C 0-4 alkyl refers to linear alkyl and branched alkyl containing 0 to 4 carbon atoms.
• Cycloalkyl or “carbocycle” refers to a monocyclic or polycyclic hydrocarbon substituent that is saturated or partially unsaturated.
• the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ -electron system;
• cycloalkyl is classified into monocyclic cycloalkyl and polycyclic cycloalkyl, and is preferably cycloalkyl containing 3 to 12, 3 to 8, or 3 to 6 carbon atoms.
• C 3-12 cycloalkyl refers to cycloalkyl containing 3 to 12 carbon atoms
• C 3-6 cycloalkyl refers to cycloalkyl containing 3 to 6 carbon atoms
• C 6-10 cycloalkyl refers to cycloalkyl containing 6 to 10 carbon atoms
• C 5-8 cycloalkyl refers to cycloalkyl containing 5 to 8 carbon atoms
• C 5-6 cycloalkyl refers to cycloalkyl containing 5 to 6 carbon atoms
• fused cycloalkyl refers to an all-carbon polycyclic group in which each ring shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably, 1, 2 or 3) double bonds, but none of them has a fully conjugated ⁇ -electron system. According to the number of formed rings, the fused cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:
• Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected to each other, wherein these rings may contain one or more (preferably, 1, 2 or 3) double bonds, but none of them has a fully conjugated ⁇ -electron system. According to the number of formed rings, the bridged cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:
• the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, which includes, but is not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
• Heterocyclyl or “heterocycle” refers to a monocyclic or polycyclic hydrocarbon substituent that is saturated or partially unsaturated.
• heterocyclyl is one containing 3 to 12, 3 to 8, 3 to 6 or 5 to 6 ring atoms; for example, "3-6 membered heterocyclyl” refers to a cyclic group containing 3 to 6 ring atoms, “5-6 membered heterocyclyl” refers to a cyclic group containing 5 to 6 ring atoms, “4-8 membered heterocyclyl” refers to a cyclic group containing 4 to 8 ring atoms, “5-10 membered heterocyclyl” refers to a cyclic group containing 5 to 10 ring atoms, “5-8 membered heterocyclyl” refers to a cyclic group containing 5 to 8 ring atoms, “4-10 membered heterocyclyl” refers to a cyclic group containing 4 to 10 ring atoms, and “3-12 membered heterocyclyl” refers to a cyclic group containing 3 to 12 ring atoms.
• Monocyclic heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
• Polycyclic heterocyclyl includes spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl.
• the spiroheterocyclyl may be monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl.
• Spiroheterocyclyl includes, but is not limited to:
• the fused heterocycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:
• the bridged heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:
• heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, including but not limited to:
• Aryl or "aromatic ring” refers to an all-carbon monocyclic or fused-polycyclic group (i.e., rings that share a pair of adjacent carbon atoms) and a polycyclic group having a conjugated ⁇ -electron system (i.e., rings with adjacent pairs of carbon atoms), and is preferably all-carbon aryl containing 6 to 10, 6 to 8 or 6 carbons atoms.
• C 6-10 aryl refers to all-carbon aryl containing 6 to 10 carbon atoms
• C 6-8 aryl refers to all-carbon aryl containing 6 to 8 carbon atoms.
• the aryl or aromatic ring includes, but is not limited to, phenyl and naphthyl.
• the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, including but not limited to:
• Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (wherein r is an integer of 0, 1 or 2), and is preferably a heteroaromatic system containing 5 to 10, 5 to 8 or 5 to 6 ring atoms.
• heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O) r (wherein r is an integer of 0, 1 or 2), and is preferably a heteroaromatic system containing 5 to 10, 5 to 8 or 5 to 6 ring atoms.
• r is an integer of 0, 1 or 2
• the heteroaryl includes, but is not limited to, furyl, thiophenyl, pyridyl, pyrrolyl, N -alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
• the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring, including but not limited to:
• Alkenyl refers to alkyl defined as above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and is preferably linear or branched alkenyl containing 2 to 10 or 2 to 4 carbon atoms.
• C 2-10 alkenyl refers to linear or branched alkenyl containing 2 to 10 carbon atoms
• C 2-4 alkenyl refers to linear or branched alkenyl containing 2 to 4 carbon atoms.
• the alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
• Alkynyl refers to alkyl defined as above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and is preferably linear or branched alkynyl containing 2 to 10 or 2 to 4 carbon atoms.
• C 2-10 alkynyl refers to linear or branched alkynyl containing 2 to 10 carbon atoms
• C 2-4 alkynyl refers to linear or branched alkynyl containing 2 to 4 carbon atoms.
• the alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
• Alkoxy refers to -O-alkyl, wherein the alkyl is defined as above.
• C 1-10 alkoxy refers to alkoxy containing 1 to 10 carbon atoms
• C 1-4 alkoxy refers to alkoxy containing 1 to 4 carbon atoms.
• the alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, butoxy and the like.
• Cycloalkyloxy refers to -O-cycloalkyl, wherein the cycloalkyl is defined as above.
• C 3-12 cycloalkyloxy refers to cycloalkyloxy containing 3 to 12 carbon atoms
• C 3-8 cycloalkyloxy refers to cycloalkyloxy containing 3 to 8 carbon atoms.
• the cycloalkyloxy includes, but is not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.
• Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is defined as above, and heterocyclyloxy includes, but is not limited to, azacyclobutyloxy, oxacyclobutyloxy, azacyclopentyloxy, nitrogen, oxacyclohexyloxy, etc.
• C 1-10 alkanoyl refers to a monovalent atomic group which is obtained after hydroxy is removed from C 1-10 alkyl acid, and is also generally referred to as "C 0-9 alkyl-C(O)-".
• C 1 alkyl-C(O)- refers to acetyl
• C 2 alkyl-C(O)- refers to propionyl
• C 3 alkyl-C(O)- refers to butyryl or isobutyryl.
• C 1-4 refers to “C 1-4 alkyl”
• C 0-4 refers to “C 0-4 alkyl”
• C 1-8 refers to “C 1-8 alkyl”
• C 0-8 refers to "C 0-8 alkyl”, which are defined as above.
• C 1-10 haloalkyl refers to an alkyl group having 1 to 10 carbon atoms in which hydrogens on the alkyl are optionally substituted with a fluorine, chlorine, bromine or iodine atom, including but not limited to, difluoromethyl (-CHF 2 ), dichloromethyl (-CHCl 2 ), dibromomethyl (-CHBr 2 ), trifluoromethyl (-CF 3 ), trichloromethyl (-CCl 3 ), tribromomethyl (-CBr 3 ), etc.
• C 1-10 haloalkoxy refers to an alkoxy group having 1 to 10 carbon atoms in which hydrogens on the alkyl are optionally substituted with a fluorine, chlorine, bromine or iodine atom, including but not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
• C 1-10 deuterioalkyl refers to an alkyl group having 1 to 10 carbon atoms in which hydrogens on the alkyl are optionally substituted with a deuterium atom, including but not limited to, monodeuteriomethyl (-CH 2 D), dideuteriomethyl (-CHD 2 ), trideuteriomethyl (-CD 3 ), etc.
• C 1-10 deuterioalkyl refers to an alkyl group having 1 to 10 carbon atoms in which hydrogens on the alkyl are optionally substituted with a deuterium atom, including but not limited to, monodeuteriomethoxy, dideuteriomethoxy, trideuteriomethoxy, etc.
• Halogen refers to fluorine, chlorine, bromine or iodine.
• EtOAc refers to ethyl acetate.
• PE refers to petroleum ether.
• DMF dimethylformamide.
• heterocyclyl group optionally substituted with alkyl means that alkyl may be, but not necessarily, present, and that the description includes instances where the heterocyclyl group is or is not substituted with alkyl.
• substituted means that one or more hydrogen atoms in the group are each independently substituted by a corresponding number of substituents. It goes without saying that a substituent is only in its possible chemical position and consistent with chemical valence bond theory, and those skilled in the art will be able to determine (by studies or theories) possible or impossible substitution without undue efforts. For example, it may be unstable when amino or hydroxy having free hydrogen is bound to a carbon atom having an unsaturated bond (such as olefin).
• Stepoisomers refer to isomers produced by different spatial arrangements of atoms in molecules, and can be classified into cis-trans isomers and enantiomers, and also into enantiomers and diastereomers. Stereoisomers resulting from rotation of single bonds are referred to as conformational stereo-isomers and sometimes also as rotamers. Stereoisomers resulting from bond lengths, bond angles, intramolecular double bonds, rings and the like are referred to as configuration stereo-isomers, and the configuration stereo-isomers are classified into two categories.
• geometric isomers resulting from the fact that a double bond or a single bond of a ring-forming carbon atom cannot rotate freely
• cis-trans isomers a pair of geometric isomers
• the compounds of the present invention may be understood to comprise the E and/or Z forms if they contain a double bond, as not specifically indicated.
• Stereoisomers having different optical rotation properties due to the absence of anti-axisymmetry in the molecule are referred to as optical isomers, and are classified into R and S configurations.
• the term "stereoisomer" may be understood to include one or more of the above enantiomers, configuration isomers and conformational isomers, unless otherwise specified, preferably S configuration.
• “Pharmaceutically acceptable salt” as used herein refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic and organic acid salts, which may be prepared by methods known in the art.
• “Pharmaceutical composition” refers to a mixture containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or pro-drug thereof, and other chemical components, for example physiologically/pharmaceutically acceptable carriers and excipients.
• the purpose of the pharmaceutical composition is to promote the administration to an organism, which facilitates the absorption of the active ingredient, thereby exerting biological activities.
• the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).
• NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
• the NMR determination is conducted by using a Bruker AVANCE-400/500 nuclear magnetic resonance apparatus, with hexadeuterodimethyl sulfoxide (DMSO- d 6 ), tetradeuteromethanol (MeOH- d 4 ), and deuterated chloroform (CDCl 3 ) as determination solvents, and tetramethylsilane (TMS) as an internal standard.
• DMSO- d 6 hexadeuterodimethyl sulfoxide
• MeOH- d 4 tetradeuteromethanol
• CDCl 3 deuterated chloroform
• TMS tetramethylsilane
• the LC-MS determination is conducted by using an Agilent 6120 mass spectrometer.
• the HPLC determination is conducted by using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 * 4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6 mm chromatographic column).
• a Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is adopted as a thin layer chromatography (TLC) silica gel plate.
• TLC thin layer chromatography
• the specification adopted by the TLC is 0.15-0.20 mm, and the specification adopted by the thin layer chromatography for product separation and purification is 0.4-0.5 mm.
• the Yantai Yellow Sea silica gel of 200-300 mesh is generally utilized as a carrier in column chromatography.
• 2,4-difluoro-1-iodobenzene (7.96 g, 33.18 mmol), (3-aminophenyl)boronic acid (5.0 g, 36.50 mmol), potassium carbonate (13.74 g, 99.54 mmol) and palladium acetate (372 mg, 1.66 mmol) were added in a mixture of ethanol and water (100 mL, 3:1), and then the mixture was stirred at room temperature under nitrogen protection for 18 hrs. After the reaction was completed, the reaction mixture was diluted with water and extracted with EtOAc.
• Intermediates 3-17 can be prepared by referring to the preparation method for intermediate 1 or 2: Intermediate No. Structural formula Chemical name [M+H] + 3 3-(5-fluoropyridin-2-yl) aniline 189.1 4 3-(3,5-difluoropyridin-2 -yl)aniline 207.3 5 5-(3,5-difluoropyridin-2 -yl)-2-fluoroaniline 225.1 6 2',4,4'-trifluoro-[1,1'-bi phenyl]-3-amine 224.2 7 2',4',6'-trifluoro-[1,1'-bi phenyl]-3-amine 224.2 8 2',6'-difluoro-[1,1'-biph enyl]-3-amine 206.2 9 3-(6-fluoropyridin-3-yl) aniline 189.2 10 2',4',6-trifluoro-[1,1'-bi phenyl]-3
• Intermediates 20-22 can be prepared by referring to the preparation method for intermediate 19: Intermediate No. Structural formula Chemical name [M+H] + 20 2-(2,4-difluorophen yl)pyridin-4-amine 207.0 21 5-(2-fluorophenyl)p yridin-3-amine 189.0 22 5-(2,6-difluorophen yl)pyridin-3-amine 207.0
• Step 1 Synthesis of tert -butyl-(2-(2,6-difluorophenyl)pyridin-4-yl)carbamate
• Intermediate 25 was prepared by synthesis of selecting corresponding starting materials by referring to the preparation method in intermediate 24.
• Step 2 Synthesis of N -(2',4'-difluoro-[1,1'-biphenyl]-3-yl)-7-fluoro-6-nitroquinazolin-4-amine
• Step 3 Synthesis of N -(2',4'-difluoro-[1,1'-biphenyl]-3-yl)-7-(3-morpholinopropoxy)-6-nitroquinazolin-4-amine
• 3-morpholinopropan-1-ol (327 mg, 2.26 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (90 mg, purity: 60%, 2.26 mmol) was added, and the reaction mixture was stirred at room temperature under nitrogen protection for 10 min.
• Step 4 Synthesis of N 4 -(2',4'-difluoro-[1,1'-biphenyl]-3-yl)-7-(3-morpholinopropoxy)quinazoline-4,6-di amine
• Step 5 Synthesis of N -(4-((2',4'-difluoro-[1,1'-biphenyl]-3-yl)amino)-7-(3-morpholinopropoxy)quinazol in-6-yl)acrylamide
• N 4 -(2',4'-difluoro-[1,1'-biphenyl]-3-yl)-7-(3-morpholinopropoxy)quinazoline-4,6-di amine 100 mg, 0.19 mmol
• triethylamine 187 mg, 1.86 mmol
• acryloyl chloride 20 mg, 0.22 mmol
• the reaction mixture was stirred at room temperature for 30 min, then supplemented with acryloyl chloride (20 mg, 0.22 mmol) and triethylamine (187 mg, 1.86 mmol), and stirred for 30 min.
• 3-morpholinopropan-1-ol (2.78 g, 19.0 mmol) was dissolved in THF (10 mL), NaH (0.80 g, 22.0 mmol, 60% purity) was added portionwise at 0 °C under nitrogen protection, and the reaction mixture was stirred for 0.5 hrs, added with 7-fluoro-6-nitroquinazolin-4-ol (2.0 g, 9.6 mmol), and heated to 75 °C and stirred for 1 hr.
• Step 3 Synthesis of N -(5-(3,5-difluoropyridin-2-yl)-2-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroq uinazolin-4-amine
• Step 4 Synthesis of N 4 -(5-(3,5-difluoropyridin-2-yl)-2-fluorophenyl)-7-(3-morpholinopropoxy)quinazol ine-4,6-diamine
• N-(5 -(3,5-difluoropyridin-2-yl)-2-fluorophenyl)-7-(3-morpholinopropoxy)-6-nitroq uinazolin-4-amine (0.30 g, 0.56 mmol) was dissolved in MeOH/H 2 O (8 mL/2 mL), the reaction mixture was added with iron powder (0.15 g, 2.8 mmol) and NH 4 Cl solid (0.30 g, 5.6 mmol), heated to 70 °C under nitrogen protection, and stirred for 2 hrs.
• Step 5 Synthesis of N -(4-((5-(3,5-difluoropyridin-2-yl)-2-fluorophenyl)amino)-7-(3-morpholinopropoxy )quinazolin-6-yl)acrylamide
• Examples 3-64 can be prepared by selecting corresponding starting materials by referring to all or part of the synthesis method in Example 1 or 2.
• Step 1 Synthesis of 7-fluoro- N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitroquinazolin-4-amine
• Step 2 Synthesis of ( R )- N -(2-(2-fluorophenyl)pyridin-4-yl)-7-((1-methylpyrrolidin-3-yl)oxy)-6-nitroqui toolin-4-amine
• Step 3 Synthesis of ( R )- N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-7-((1-methylpyrrolidin-3-yl)oxy)quinazolin e-4,6-diamine
• Step 4 Synthesis of ( R )- N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-((1-methylpyrrolidin-3-yl)oxy) quinazolin-6-yl)acrylamide
• Examples 68-91 can be prepared by selecting corresponding starting materials by referring to all or part of the synthesis method in Example 65.
• Example No. Structural formula Chemical name [M+H] + 68 N -(4-((2-(2-fluorophenyl)pyrid in-4-yl)amino)-7-(2-morpholin oethoxy)quinazolin-6-yl)acryla mide 515.2 69 N -(4-((2-(2-fluorophenyl)pyrid in-4-yl)amino)-7-(3-morpholin opropoxy)quinazolin-6-yl)acryl amide 529.2 70 N -(4-((2-(2-fluorophenyl)pyrid in-4-yl)amino)-7-(3-(4-methylp iperazin-1-yl)propoxy)quinazol in-6-yl)acrylamide 542.2 71 N -(7-(3-(4-
• Step 1 Synthesis of 7-fluoro- N 4 -(2-(2-fluorophenyl)pyridin-4-yl)quinazoline-4,6-diamine
• Step 2 Synthesis of N -(7-fluoro-4-((2-(2-fluorophenyl)pyridin-4-yl)amino)quinazolin-6-yl)acrylamide
• reaction mixture was supplemented with 2-fluoroacrylic acid (46 mg, 0.51 mmol), HATU (195 mg, 0.51 mmol) and a solution of triethylamine (86 mg, 0.86 mmol) in DMF (5 mL).
• Step 1 Synthesis of N -(2-(2-fluorophenyl)pyridin-4-yl)-7-morpholino-6-nitroquinazolin-4-amine
• Step 2 Synthesis of N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-7-morpholinoquinazoline-4,6-diamine
• N -(2-(2-fluorophenyl)pyridin-4-yl)-7-morpholino-6-nitroquinazolin-4-amine (0.47 g, 0.89 mmol) was dissolved in methanol (30 mL), then Pd/C (0.10 g) was adde d in one portion, and the reaction mixture was replaced with hydrogen for three times and then heated to 40 °C under the hydrogen atmosphere and reacted ov ernight, then cooled to room temperature, and filtered through celite, and the filtr ate was concentrated to obtain the crude product N 4 -(2-(2-fluorophenyl)pyridin-4-y l)-7-morpholinoquinazoline-4,6-diamine (0.33 g, yield: 78%).
• Step 3 Synthesis of N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-morpholinoquinazolin-6-yl)acryla mide
• N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-7-morpholinoquinazoline-4,6-diamine (0.13 g, 0.28 mmol) was dissolved in DMF (4 mL), then 2-fluoroacrylic acid (50 ⁇ g, 0.55 mmol), HATU (0.21 g, 0.55 mmol) and DIPEA (0.14 mL, 0.83 mmol) were added, and the reaction mixture was heated to 40 °C and stirred for 1 hr.
• Examples 96-110 can be prepared by selecting corresponding starting materials by referring to all or part of the synthesis method in Example 94 or 95.
• Example No. Structural formula Chemical name [M+H] + 96 N -(4-((2-(2-fluorophenyl)pyridi n-4-yl)amino)-7-(4-hydroxypip eridin-1-yl)quinazolin-6-yl)acr ylamide 485.2 97 N -(4-((2-(2-fluorophenyl)pyridi n-4-yl)amino)-7-(4-methylpiper azin-1-yl)quinazolin-6-yl)acryl amide 484.2 98 N- (4-((2-(2-fluorophenyl)pyridi n-4-yl)amino)-7-(4-morpholino piperidin-1-yl)quinazolin-6-yl) acrylamide 554.2 99
• Example 111 preparation of ( R )- N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-((1-(2-methoxyethyl)pyrrolidin -3-yl)oxy)quinazolin-6-yl)acrylamide
• Step 1 Synthesis of tert -butyl ( R )-3-((4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-yl)oxy)pyrro lidine-1-carboxylate
• Step 2 Synthesis of tert-butyl ( R )-3-((6-amino-4-((2-(2-fluorophenyl)pyridin-4-yl)amino)quinazolin-7-yl)oxy)pyrr olidine-1-carboxylate
• Step 3 Synthesis of tert -butyl ( R )-3-((6-acrylamido-4-((2-(2-fluorophenyl)pyridin-4-yl)amino)quinazolin-7-yl)oxy ) pyrrolidine-1-carboxylate
• Step 4 Synthesis of ( R )- N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-(pyrrolidin-3-oxy)quinazolin-6-yl)acrylamide trifluoroacetate
• Step 5 Synthesis of ( R )- N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-((1-(2-methoxyethyl)pyrrolidin -3-yl)oxy)quinazolin-6-yl)acrylamide
• Step 1 Synthesis of ( R )- N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitro-7-(pyrrolidin-3-oxy)quinazolin-4-a mine
• Step 2 Synthesis of ( R )-7-((1-cyclopropylpyrrolidin-3-yl)oxy)- N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitr oquinazolin-4-amine
• Step 3 Synthesis of ( R )-7-((1-cyclopropylpyrrolidin-3-yl)oxy)- N 4 -(2-(2-fluorophenyl)pyridin-4-yl)quina zoline-4,6-diamine
• Step 4 Synthesis of ( R )- N -(7-((1-cyclopropylpyrrolidin-3-yl)oxy)-4-((2-(2-fluorophenyl)pyridin-4-yl)am ino)quinazolin-6-yl)acrylamide
• Examples 115-121 can be prepared by selecting corresponding starting materials by referring to all or part of the synthesis method in Example 95, 113 or 114.
• Example 122 Preparation of N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide
• Step 1 Synthesis of tert -butyl 4-(3-((4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-yl)oxy)propyl )piperazine-1-carboxylate
• Step 2 Synthesis of N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitro-7-(3-(piperazin-1-yl)propoxy)quinazolin -4-amine
• Step 3 Synthesis of N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitro-7-(3-(4-(2-((tetrahydro-2 H -pyran-2-yl)o xy)ethyl)piperazin-1-yl)propoxy)quinazolin-4-amine
• N -(2-(2-fluorophenyl)pyridin-4-yl)-6-nitro-7-(3-(piperazin-1-yl) propoxy)quinazolin-4-amine (0.50 g, 0.99 mmol) in N
• N -dimethylacetamide 10 m L
• 2-(2-bromoethoxy)tetrahydro-2 H -pyran (0.15 mL, 0.99 mmol
• pota ssium carbonate (0.41 g, 2.96 mmol
• potassium iodide 0.16 g, 0.99 mmol
• Step 4 Synthesis of N 4 -(2-(2-fluorophenyl)pyridin-4-yl)-7-(3-(4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethy l)piperazin-1-yl)propoxy)quinazoline-4,6-diamine
• Step 5 Synthesis of N-(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-(3-(4-(2-((tetrahydro-2 H -pyran-2-y l)oxy)ethyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide
• Step 6 Synthesis of N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide
• N -(4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-7-(3-(4-(2-((tetrahydro-2 H -pyran-2-yl)oxy)ethyl)piperazin-1-yl)propoxy)quinazolin-6-yl)acrylamide (0.22 g, 0.32 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.08 mL, 14.5 mmol) was added, and the reaction mixture was reacted at room temperature for 1.5 hrs.
• Examples 123-125 can be prepared by selecting corresponding starting materials by referring to all or part of the synthesis method in Example 122.
• Cell lines Cell culture medium Cell density 1 A431 DMEM+15%FBS 5000 2 Ba/F3 EGFR-D770-N771ins_SVD RPMI1640+10%FBS 3000 3 Ba/F3 EGFR-V769_D770insASV RPMI1640+10%FBS 3000
• the series of compounds of the present invention have a strong inhibition effect on insertion, deletion or other mutations of EGFR Exon 20 at cellular level and have high selectivity for EGFR WT.

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